SGEF forms a complex with Scribble and Dlg1 and regulates epithelial junctions and contractility.

The canonical Scribble polarity complex is implicated in regulation of epithelial junctions and apical polarity. Here, we show that SGEF, a RhoG-specific GEF, forms a ternary complex with Scribble and Dlg1, two members of the Scribble complex. SGEF targets to apical junctions in a Scribble-dependent fashion and functions in the regulation of actomyosin-based contractility and barrier function at tight junctions as well as E-cadherin-mediated formation of adherens junctions. Surprisingly, SGEF does not control the establishment of polarity. However, in 3D cysts, SGEF regulates the formation of a single open lumen. Interestingly, SGEF's nucleotide exchange activity regulates the formation and maintenance of adherens junctions, and in cysts the number of lumens formed, whereas SGEF's scaffolding activity is critical for regulation of actomyosin contractility and lumen opening. We propose that SGEF plays a key role in coordinating junctional assembly and actomyosin contractility by bringing together Scribble and Dlg1 and targeting RhoG activation to cell-cell junctions.

Anillin regulates epithelial cell mechanics by structuring the medial-apical actomyosin network.

Cellular forces sculpt organisms during development, while misregulation of cellular mechanics can promote disease. Here, we investigate how the actomyosin scaffold protein anillin contributes to epithelial mechanics in Xenopus laevis embryos. Increased mechanosensitive recruitment of vinculin to cell-cell junctions when anillin is overexpressed suggested that anillin promotes junctional tension. However, junctional laser ablation unexpectedly showed that junctions recoil faster when anillin is depleted and slower when anillin is overexpressed. Unifying these findings, we demonstrate that anillin regulates medial-apical actomyosin. Medial-apical laser ablation supports the conclusion that that tensile forces are stored across the apical surface of epithelial cells, and anillin promotes the tensile forces stored in this network. Finally, we show that anillin's effects on cellular mechanics impact tissue-wide mechanics. These results reveal anillin as a key regulator of epithelial mechanics and lay the groundwork for future studies on how anillin may contribute to mechanical events in development and disease.

Thrombin generation assay identifies individual variability in responses to low molecular weight heparin in pregnancy: implications for anticoagulant monitoring.

Low molecular weight heparin (LMWH) given to inhibit coagulation and reduce the risk of thrombosis, is typically monitored by anti-Xa assay. However, anti-Xa levels may not necessarily provide an accurate measure of coagulation inhibition. Moreover, pregnancy is associated with hypercoagulability, which may compromise the efficacy of LMWH. We looked at the association between anti-Xa levels and parameters of thrombin generation assay [TGA; area under the curve (AUC), peak height (PH) and time to peak (ttP)] using samples from 41 pregnant women receiving LMWH and 40 normal pregnant women controls. TGA results confirmed the physiological hypercoagulability of normal pregnancy (mean normalised values: AUC 119%; PH 157%; ttP 72%). Although anti-Xa measures correlated with all three TGA parameters, this group correlation masked significant inter-individual variability, demonstrated by the R(2) value or coefficient of determination. Anti-Xa levels contributed to 74% of variation in AUC values, 63% of variation in PH values and only 53% of variation in ttP values. The remainder reflects the contribution of patients' intrinsic coagulation status. Hence, some patients with 'safe' anti-Xa levels may potentially be under-anticoagulated, particularly in pregnancy. Measuring coagulability directly with TGA may lower the risk of adverse events due to under-anticoagulation in selected patients.

Menstrual problems and contraception in women of reproductive age receiving oral anticoagulation.

BACKGROUND: Oral anticoagulation is associated with increased bleeding complications. The aim of this study was to assess the changes in menstrual loss and pattern in women taking anticoagulant treatment. STUDY DESIGN: Women on oral anticoagulant (OA) treatment at the Royal Free Hospital were interviewed and completed a questionnaire about their menstrual cycle before and after commencing oral anticoagulation treatment. They were then asked to complete a pictorial bleeding assessment chart (PBAC) during their next menstrual bleeding episode. RESULTS: Fifty-three women between the ages of 20 and 50 years participated in the study. Of these, 47 women completed a PBAC. The mean duration of menstruation increased from 5 days before starting OA therapy to 7 days after the commencement of treatment. Thirty-one (66%) of the 47 women who completed the PBAC had a score that was greater than 100. The number of women who experienced flooding or clots during menstruation and intermenstrual or postcoital bleeding also increased. In total, 29 (54.7%) women changed their method of contraception during OA treatment. Seventeen women who did not want to become pregnant were not using contraception, including 10 women who were on hormonal contraception prior to starting anticoagulant therapy. CONCLUSION: Women of reproductive age experience heavy and prolonged menstrual bleeding whilst on OA therapy. Women of reproductive age on OA therapy should be monitored for menstrual disorders to ensure that prompt and appropriate treatment is instituted. Advice about appropriate contraception should also be part of the medical care provided for these women. Barrier contraception, sterilization and progestin-only contraception are all suitable methods of contraception in this patient group.

Levonorgestrel-releasing intrauterine system for the management of heavy menstrual bleeding in women with inherited bleeding disorders: long-term follow-up.

BACKGROUND: There are currently limited data on the use of the levonorgestrel-releasing intrauterine system (LNG-IUS) for the management of heavy menstrual bleeding (HMB) in women with inherited bleeding disorders (IBDs) particularly on its long-term (>12 months) efficacy. STUDY DESIGN: This study involves a case series of women with IBDs who received the LNG-IUS as treatment for HMB. Menstrual blood loss before its insertion and at the time of follow-up was assessed by the pictorial blood-loss assessment chart (PBAC) and hemoglobin (Hb) concentrations. A questionnaire was used to evaluate quality of life (QOL) during menstruation before and after insertion of the LNG-IUS. RESULTS: Twenty-six women were included. The median duration of LNG-IUS use at follow-up was 33 months (range, 14-103). The median PBAC score decreased from 255 (range, 134-683) to 35 (range, 0-89) with LNG-IUS use. The median Hb concentrations (11.2 to 13.2 g/dL) and QOL scores (median, 26 to 52) improved significantly with LNG-IUS use (p<.01). CONCLUSION: The LNG-IUS appears to be an effective long-term treatment for HMB in women with IBDs.